tbuckley/cabot-search huggingface dataset:
Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein
Authors: Fang Ye, Thian‐Sze Wong, Geng Chen, Zhiyi Zhang, Binghao Zhang, Shiyi Gan, Wei Gao, Jiancheng Li, Zhangsong Wu, Xin Pan, Yang Du
Journal: MedComm (2022)

GPR17 is a class A orphan G protein-coupled receptor (GPCR) expressed in neurons and oligodendrocyte progenitors of the central nervous system (CNS). The signalling of GPR17 occurs through the heterotrimeric Gi, but its activation mechanism is unclear. Here, we employed cryo-electron microscopy (cryo-EM) technology to elucidate the structure of activated GPR17-Gi complex. The 3.02 Å resolution structure, together with mutagenesis studies, revealed that the extracellular loop2 of GPR17 occupied the orthosteric binding pocket to promote its self-activation. The active GPR17 carried several typical microswitches like other class A GPCRs. Moreover, the Gi interacted with the key residues of transmembrane helix 3 (TM3), the amphipathic helix 8 (Helix8), and intracellular loops 3 (ICL3) in GPR17 to engage in the receptor core. In summary, our results highlight the activation mechanism of GPR17 from the structural basis. Elucidating the structural and activation mechanism of GPR17 may facilitate the pharmacological intervention for acute/chronic CNS injury.
Effects of Selenium Supplementation for Cancer Prevention in Patients With Carcinoma of the Skin
Authors: Larry C. Clark
Journal: JAMA (1996)

<h3>Objective.</h3> —To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. <h3>Design.</h3> —A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. <h3>Setting.</h3> —Seven dermatology clinics in the eastern United States. <h3>Patients.</h3> —A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. <h3>Interventions.</h3> —Oral administration of 200 μg of selenium per day or placebo. <h3>Main Outcome Measures.</h3> —The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. <h3>Results.</h3> —After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR, 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. <h3>Conclusions.</h3> —Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made.
Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): short-term outcomes of a multicentre randomised controlled trial
Authors: Qingyang Feng, Weitang Yuan, Taiyuan Li, Bo Tang, Baoqing Jia, Yanbing Zhou, Wei Zhang, Ren Zhao, Cheng Zhang, Longwei Cheng, Xiaoqiao Zhang, Fei Liang, Guodong He, Ye Wei, Jianmin Xu
Journal: The Lancet. Gastroenterology & hepatology (2022)
Patients' Ratings of Outpatient Visits in Different Practice Settings
Authors: Haya R. Rubin
Journal: JAMA (1993)

<h3>Objective.</h3> —To determine how patients in different kinds of practices—solo or single specialty (SOLO), multispecialty group (MSG), or health maintenance organizations (HMOs)—and with fee-for-service (FFS) or prepaid physician payment arrangements evaluate their medical care. <h3>Design.</h3> —Survey of adult outpatients after office visits, with sample weighted to represent population of patients visiting physicians in each practice type. <h3>Setting.</h3> —Offices of 367 internists, family practitioners, endocrinologiste, cardiologists, and nurse practitioners, in HMOs (prepaid only), MSGs (prepaid and FFS), and SOLO practices (prepaid and FFS). <h3>Patients.</h3> —Adults (N=17671) at start of the Medical Outcomes Study. <h3>Outcome Measures.</h3> —Overall rating of the visit (five choices from excellent to poor). A random half of the sample also rated the provider's technical skills, personal manner, and explanations of care as well as time spent during the visit, the appointment wait, the office wait, the convenience of the office location, and telephone access. <h3>Results.</h3> —Fifty-five percent of patients rated their visit overall as excellent, 32% very good, 11% good, and 2% fair or poor. Patients of SOLO practitioners were more likely (64%) to rate their visit excellent than MSG (48%) or HMO (49%) patients (<i>P</i>&lt;.001 ). Patients of SOLO practitioners rated all aspects of care better than HMO patients did, most markedly appointment waits (64% vs 40% excellent;<i>P</i>&lt;.0001) and telephone access (64% vs 33% excellent;<i>P</i>&lt;.0001). Within SOLO and MSG practices, FFS patients rated most specific aspects better than prepaid patients, but these differences were not statistically significant and were inconsistent across cities. Adjusting for patients' demographics, diagnoses and self-rated health did not change results. Physicians with visit ratings in the lowest 20% were nearly four times as likely to be left by patients within 6 months than physicians in the highest 20% (16.7% vs 4.6%;<i>P</i>&lt;.001). <h3>Conclusion.</h3> —Of the five practice type and payment method combinations, SOLO FFS patients rated their visits best and HMO patients worst. Whether FFS or prepaid, care was rated better in small than in large practices. Our study shows that a brief visit rating form can be used to compare practice settings and health plans, and that patient ratings predict what proportion of patients, on average, will leave their physicians in the next several months. (<i>JAMA</i>. 1993;270:835-840)
Evaluating the efficacy and safety of SpikoGen®, an Advax-CpG55.2–adjuvanted severe acute respiratory syndrome coronavirus 2 spike protein vaccine: a phase 3 randomized placebo-controlled trial
Authors: Payam Tabarsi, Nassim Anjidani, Ramin Shahpari, Masoud Mardani, Araz Sabzvari, Babak Yazdani, Hamidreza Kafi, Newsha Fallah, Ali Ebrahimi, Ali Taheri, Nikolai Petrovsky, Saghar Barati
Journal: Clinical Microbiology and Infection (2022)
Graphdiyne-Related Materials in Biomedical Applications and Their Potential in Peripheral Nerve Tissue Engineering
Authors: Xiao Li, Huiquan Jiang, Ning He, Wei-En Yuan, Yun Qian, Yuanming Ouyang
Journal: Cyborg and Bionic Systems (2022)

Graphdiyne (GDY) is a new member of the family of carbon-based nanomaterials with hybridized carbon atoms of sp and sp2, including α, β, γ, and (6,6,12)-GDY, which differ in their percentage of acetylene bonds. The unique structure of GDY provides many attractive features, such as uniformly distributed pores, highly π-conjugated structure, high thermal stability, low toxicity, biodegradability, large specific surface area, tunable electrical conductivity, and remarkable thermal conductivity. Therefore, GDY is widely used in energy storage, catalysis, and energy fields, in addition to biomedical fields, such as biosensing, cancer therapy, drug delivery, radiation protection, and tissue engineering. In this review, we first discuss the synthesis of GDY with different shapes, including nanotubes, nanowires, nanowalls, and nanosheets. Second, we present the research progress in the biomedical field in recent years, along with the biodegradability and biocompatibility of GDY based on the existing literature. Subsequently, we present recent research results on the use of nanomaterials in peripheral nerve regeneration (PNR). Based on the wide application of nanomaterials in PNR and the remarkable properties of GDY, we predict the prospects and current challenges of GDY-based materials for PNR.
Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial
Authors: Elisabeth Livingstone, Lisa Zimmer, Jessica C Hassel, Michael Fluck, Thomas K Eigentler, Carmen Loquai, Sebastian Haferkamp, Ralf Gutzmer, Friedegund Meier, Peter Mohr, Axel Hauschild, Bastian Schilling, Christian Menzer, Felix Kiecker, Edgar Dippel, Alexander Roesch, Mirjana Ziemer, Beate Conrad, Silvia Körner, Christine Windemuth-Kieselbach, Leonora Schwarz, Claus Garbe, Jürgen C Becker, Dirk Schadendorf, Elisabeth Livingstone, Lisa Zimmer, Jessica C Hassel, Michael Fluck, Thomas K Eigentler, Carmen Loquai, Sebastian Haferkamp, Ralf Gutzmer, Friedegund Meier, Peter Mohr, Axel Hauschild, Bastian Schilling, Christian Menzer, Felix Kiecker, Edgar Dippel, Alexander Roesch, Mirjana Ziemer, Beate Conrad, Silvia Körner, Jan-Christoph Simon, Rudolf A Herbst, Carola Berking, Jochen Utikal, Sabine Sell, Uwe M Martens, Patrick Terheyden, Rudolf Stadler, Christine Windemuth-Kieselbach, Leonora Schwarz, Claus Garbe, Jürgen C Becker, Dirk Schadendorf
Journal: The Lancet (2022)
Adenovirus disease after hematopoietic cell transplantation: A Japanese transplant registry analysis
Authors: Yoshihiro Inamoto, Wataru Takeda, Tsuneaki Hirakawa, Hirotoshi Sakaguchi, Nobuaki Nakano, Naoyuki Uchida, Noriko Doki, Kazuhiro Ikegame, Yuta Katayama, Masashi Sawa, Takuro Kuriyama, Nobuhiro Hiramoto, Shuichi Ota, Yukiyasu Ozawa, Keisuke Kataoka, Yoshinobu Kanda, Moeko Hino, Takafumi Kimura, Yoshiko Atsuta, Takahiro Fukuda, Koji Nagafuji
Journal: American Journal of Hematology (2022)

We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.
Trafficking between clonally related peripheral T-helper cells and tissue-resident T-helper cells in chronic GVHD
Authors: Xiaohui Kong, Xiwei Wu, Bixin Wang, Deye Zeng, Kaniel Cassady, Ubaydah Nasri, Moqian Zheng, Alyssa Wu, Hanjun Qin, Weimin Tsai, Amandeep Salhotra, Ryotaro Nakamura, Paul J. Martin, Defu Zeng
Journal: Blood (2022)

Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T-helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. We show that in patients with cGVHD, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity. These cells augmented memory B-cell differentiation and production of immunoglobulin G via interleukin 21 (IL-21). Tph cell expansion was also observed in a murine model of cGVHD. This Tph cell expansion in the blood is associated with the expansion of pathogenic tissue-resident T-helper (Trh) cells that form lymphoid aggregates surrounded by collagen in graft-versus-host disease (GVHD) target tissues. Adoptive transfer experiments showed that Trh cells from GVHD target tissues give rise to Tph cells in the blood, and conversely, Tph cells from the blood give rise to Trh cells in GVHD target tissues. Tph cells in the blood and Trh cells in GVHD target tissues had highly overlapping T-cell receptor α and β repertoires. Deficiency of IL-21R, B-cell lymphoma 6 (BCL6), or T-bet in donor T cells markedly reduced the proportions of Tph cells in the blood and Trh cells in GVHD target tissues and reduced T-B interaction in the lymphoid aggregates. These results indicate that clonally related pathogenic Tph cells and Trh cells traffic between the blood and cGVHD target tissues, and that IL-21R-BCL6 signaling and T-bet are required for the development and expansion of Tph and Trh cells in the pathogenesis of cGVHD.
Correction to: A novel melittin nano-liposome exerted excellent anti-hepatocellular carcinoma efficacy with better biological safety
Authors: Jie Mao, Shujun Liu, Min Ai, Zhuo Wang, Duowei Wang, Xianjing Li, Kaiyong Hu, Xinghua Gao, Yong Yang
Journal: Journal of Hematology & Oncology (2022)
Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
Authors: Christian Hinze, Christine Kocks, Janna Leiz, Nikos Karaiskos, Anastasiya Boltengagen, Shuang Cao, Christopher Mark Skopnik, Jan Klocke, Jan-Hendrik Hardenberg, Helena Stockmann, Inka Gotthardt, Benedikt Obermayer, Laleh Haghverdi, Emanuel Wyler, Markus Landthaler, Sebastian Bachmann, Andreas C. Hocke, Victor Corman, Jonas Busch, Wolfgang Schneider, Nina Himmerkus, Markus Bleich, Kai-Uwe Eckardt, Philipp Enghard, Nikolaus Rajewsky, Kai M. Schmidt-Ott
Journal: Genome Medicine (2022)

Abstract Background Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. Methods We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1–2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. Results High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. Conclusions The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.
Exceptional response to PD-1 inhibition immunotherapy in advanced metastatic osteosarcoma with tumor site infection
Authors: Meng Li, Qiyuan Bao, Zhusheng Zhang, Beichen Wang, Zhuochao Liu, Junxiang Wen, Rong Wan, Yuhui Shen, Weibin Zhang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Recent clinical trials have demonstrated a lack of activity of immune checkpoint inhibitors (ICIs) against osteosarcoma. Previous clinical observations have demonstrated a potential immune-stimulatory effect of tumor site infection for osteosarcoma patients. However, whether such infection could augment the efficacy of immunotherapy such as ICIs is currently unknown. Here we report a case of a heavily pretreated 14-year-old boy with pulmonary metastatic osteosarcoma, who has suffered from multiple wound infections and thoracic empyema after previous metastasectomy. Despite the ongoing tumor site infection, the patient had a rapid and durable (11 months) remission of the metastatic lesions after the administration of the Programmed cell death-1(PD-1) inhibitor camrelizumab. No serious ICI-related toxicities or worsening of the infection were noticed during the treatment. Correlative analysis suggested that intratumoral CD8+ T cell infiltration, Programmed death-ligand 1(PD-L1) expression and IFN-γ expression were increased in the tumor microenvironment postinfection versus preinfection. Furthermore, using RNA-seq gene expression analysis, we found a variety of checkpoint targets were also upregulated such as CD200 , TIGIT , LAG3 , etc. Our report supports the hypothesis of tumor site infection as a potential synergistic mechanism in the tumor microenvironment for ICI immunotherapy.
Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol — United States, May–August 2022
Authors: Kevin O’Laughlin, Farrell A. Tobolowsky, Riad Elmor, Rahsaan Overton, Siobhán M. O’Connor, Inger K. Damon, Brett W. Petersen, Agam K. Rao, Kevin Chatham-Stephens, Patricia Yu, Yon Yu, Sarah Ahmadi, Rachel Avery, Kathryn Bean, Leah Beavers, Kim Belanger Giguere, Joi Brownlee, Catherine Campbell, Maggie Cheng, Rachel Clinton, Taylor Coleman, Monique S. Davis, Marie Dubreus, Meryl Henry, Sujeith B. Lozoya, Jahnae Morgan, Kalimah Muhammad, Corinne M. Parker, Nigel Peters, Ellery Rybak, Andrew Schwenk, Jessica van Loben Sels, Max Veillard,
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Currently, no Food and Drug Administration (FDA)-approved treatments for human monkeypox are available. Tecovirimat (Tpoxx), however, is an antiviral drug that has demonstrated efficacy in animal studies and is FDA-approved for treating smallpox. Use of tecovirimat for treatment of monkeypox in the United States is permitted only through an FDA-regulated Expanded Access Investigational New Drug (EA-IND) mechanism. CDC holds a nonresearch EA-IND protocol that facilitates access to and use of tecovirimat for treatment of monkeypox.§ The protocol includes patient treatment and adverse event reporting forms to monitor safety and ensure intended clinical use in accordance with FDA EA-IND requirements. The current multinational monkeypox outbreak, first detected in a country where Monkeypox virus infection is not endemic in May 2022, has predominantly affected gay, bisexual, and other men who have sex with men (MSM) (1,2). To describe characteristics of persons treated with tecovirimat for Monkeypox virus infection, demographic and clinical data abstracted from available tecovirimat EA-IND treatment forms were analyzed. As of August 20, 2022, intake and outcome forms were available for 549 and 369 patients, respectively; 97.7% of patients were men, with a median age of 36.5 years. Among patients with available data, 38.8% were reported to be non-Hispanic White (White) persons, 99.8% were prescribed oral tecovirimat, and 93.1% were not hospitalized. Approximately one half of patients with Monkeypox virus infection who received tecovirimat were living with HIV infection. The median interval from initiation of tecovirimat to subjective improvement was 3 days and did not differ by HIV infection status. Adverse events were reported in 3.5% of patients; all but one adverse event were nonserious. These data support the continued access to and treatment with tecovirimat for patients with or at risk for severe disease in the ongoing monkeypox outbreak.
COVID-19 vaccine effectiveness in patients with non–dialysis-dependent chronic kidney diseases: findings from a population-based observational study from British Columbia, Canada
Authors: Mohammad Atiquzzaman, Yuyan Zheng, Lee Er, Ognjenka Djurdjev, Joel Singer, Mel Krajden, Shabnam Balamchi, Doneal Thomas, Matthew J. Oliver, Adeera Levin
Journal: Kidney International (2022)